Dendritic cell (DC) production of IL-12 is thought to be a major initiation step in host resistance to Toxoplasma gondii. Previous studies had indicated that this protozoan parasite triggers IL-12 production from DC by stimulating two signaling pathways, one involving the chemokine receptor CCR5 and a second more important pathway involving the Toll-like receptor(TLR)/IL-1R adaptor molecule MyD88. This year we successfully identified this second receptor along with its parasite ligand. By biochemically separating a soluble parasite extract, we first isolated a protein with potent IL-12 inducing activity that was dependent on MyD88. When sequenced this parasite molecule was found to be a profilin, a structural protein involved in actin polymerization. Importantly, using both cell lines transfected with different TLR as well as mice with targeted knock-outs in these genes, we were able to identify TLR11 as the receptor stimulated by this ligand. Moreover, TLR11 was found to be critically required in vivo for T. gondii induced IL-12 production and optimal resistance to infection, thereby demonstrating a role for the receptor in host recognition of protozoan pathogens. This work also established profilins from apicomplexan parasites as the first known ligands for TLR11. In previous work, we identified another parasite ligand, cyclophilin 18 (C-18), involved in stimulating the CCR5 chemokine receptor that contributes to IL-12 production by DC and showed that due to its binding of this receptor it is able to block infection of T lymphocytes by R5 type HIV virus. Site-directed mutagenesis was employed to identify the domains in C-18 responsible for its CCR5 binding and antiviral functions. Two mutations situated on the face of the protein, predicted to be involved in its interaction with the ligand cyclosporin A, were shown to be critical for CCR5-binding and the inhibition of HIV-1 fusion and infectivity. In contrast, four mutations in C-18 specifically designed to abolish the peptidyl-prolyl cis-trans-isomerase activity of the protein failed to inactivate its CCR5 binding and HIV inhibitory activities. Interleukin-12 induction by C-18, on the other hand, was abrogated by mutations effecting either the CCR5 binding or enzymatic function of the molecule. These findings shed light on the structural basis of the molecular mimicry of chemokine function by a pathogen-derived protein and provide a basis for further modification of C-18 into an antiviral agent.